1. Severe Acute Respiratory Syndrome (SARS) Lydia Ho & Rui Yang BISC 209 Professor Mary Allen

2. November 16, 02 Initial cases of SARS appeared in South China February 14, 03 305 cases & 5 deaths from an unknown acute respiratory syndrome

3. March 03: New reports of outbreaks came in from Hong Kong, Singapore & Vietnam New syndrome was designated as “severe acute respiratory syndrome,” or SARS

4. March 17, 03: WHO called for global collaborative research on SARS March 12, 03: WHO issued global alert about SARS

5. March 24, 03: Scientists in CDC and HK announced isolation of new coronavirus from SARS patients DNA sequencing shows this virus is distinct from all known human pathogens

6. April 25, 03: Nearly 3000 SARS cases have been identified in China April 20-25, 03: Outbreaks in Hanoi, Hong Kong, China, Singapore & Toronto showed signs of peaking City closed down schools & imposes strict quarantine measures

8. But the investigation continues… By the end of June, 03: Most countries were removed from the list of areas with recent local transmission of SARS: Singapore, Hong Kong, Beijing, Toronto, Taiwan

9. The Pathogen behind it all … SARS-CoV Virus

10. Discovery of the new virus Kochs postulates Discovery of novel coronavirus in patient Isolation of cell culture Reproducible symptom in cell culture Identical isolates produced  Novel coronavirus is the cause of SARS

11. Coronaviridae A family of large, enveloped, positive- sense single stranded RNA virus Irregular shape Characteristic ‘club- shaped’ surface projections (~20nm)

12. SARS-CoV Genome 71% of the genome codes for polyproteins Remainder: codes for structural proteins S (spike): receptor binding, cell fusion, major antigen E (envelop): envelop-associated protein M (membrane): transmembrane-budding N (nucleocapsid): genome-associated phosphoprotein

13. SARS-CoV Genome

14. SARS-CoV Life Cycle S-protein binds to receptor  initiation of induced endocytosis Translation of viral RNA polymerase Transcription of (+) RNA into genomic and subgenomic mRNA in the cytoplasm N protein synthesized from free ribosome S and M protein synthesized in RER Budding from RER as virion, excretion from cell via Golgi

16. SARS Case Definition

17. Clinical Symptoms High fever

18. Clinical History 10 days before onset of symptoms Close contact with probable/suspected SARS patients Live in / travel to area with transmission of SARS

19. Transmission of SARS

20. Transmission of SARS-CoV Highly probable: origination is a cross- species jump from civet cat to human Human-to-human transmission Direct contact Spread in droplets shed from respiratory secretions Possible fecal transmission

21. Infectiousness of SARS Debatable Most patients are moderately infectious Cases of “superspreaders” reported Factors affecting infectiousness are Viral load of the secretion from index patient Aerosol-generation procedures Distance of the index patient

22. Methods of Diagnosis

23. Virus Detection Virus isolation: inoculate suitable cell culture with patient specimens

24. Antibody Detection When infected by SARS-CoV  antibodies (e.g. IgM and IgG) are produced / change in level Enzyme-linked immunosorbent assay (ELISA)

25. Antibody Detection Immunofluorescence assay (IFA): Sample: patient serum Method: Fix SARS-CoV-infected cells on microscope’s slide (patient antibodies already bound to viral antigens) Immunofluorescent-labeled 2 º antibodies bind to human IgG/IgM Significance: positive result after 10 days of onset of illness

26. Clinical Findings Clinical history & observation Chest radiography: important role 70-80% patients have abnormal chest radiographs Normal SARS patient

27. Method of Cure

28. Immunomodulatory therapy Corticosteroid Very powerful: affect entire body Anti-inflammatory & immunosuppressive effects Significance: early improvement of fever, better radiographic infiltrates Controversy: ? Effectiveness Adverse side effects

29. Antiviral Agents Ribavirin: nucleoside analog Most frequently administered Have antiviral activity against many DNA & RNA viruses Criticism: ? Effectiveness Adverse side effects

30. Antiviral Agents Protease inhibitor: Lopinavir-ritonavir co-formulation: protease inhibitor used to treat HIV infection With ribavirin: block processing of the viral replicase polyprotein  prevent RNA replication

31. Method of Prevention & Control

32. Principle of Disease Confinement Principle: to break the chain of transmission from infected to healthy person 3-step protocol of disease confinement Case detection Prompt isolation Contract tracing Daily health check Voluntary home isolation

33. Epidemic Containment Creation of emergency operating center Institutional support Efficient quarantine measures Legislation International collaboration—WHO Travel alerts and restrictions Coordination for research Agreement of countries on containment protocol

34. SARS and Beyond… The early management of SARS epidermic may serve as a model for the containment of future epidermics and pandemics

35. References Cann, A. (January 20, 2004). Severe acute respiratory syndrome (SARS). Retrieved from: http://www-micro.msb.le.ac.uk/3035/coronaviruses.htmlhttp://www-micro.msb.le.ac.uk/3035/coronaviruses.html Dept. of Communicable Disease Surveillance and Response, WHO. (2003). Consensus document on the epidemiology of severe acute respiratory syndrome (SARS). Kamps, Hoffmann. (October, 2003). SARS Reference. Retrieved from: www.SARSreference.com Shanghai Center for Bioinfomatics Technology. (2004). Life cycle of the SARS virus. Retrieved from: http://www.scbit.org/english/sars/Life%20cycle%20of%20SARS%20virus.htm http://www.scbit.org/english/sars/Life%20cycle%20of%20SARS%20virus.htm Siddell, S, Wege H., ter Meulen V. The biology of coronaviruses. J. Gen Virol. 1983; 64 (Pt4): 761-776 Thiel, et al. ( June 19, 2003). Mechanisms and enzymes involved in SARS coronavirus genome expression, Journal of general virology. Retrieved from: http://www.socgenmicrobiol.org.uk/JGVDirect/19424/19424ft.htm http://www.socgenmicrobiol.org.uk/JGVDirect/19424/19424ft.htm Tsang KW, Ho PL, Ooi GC, Yee WK, et al. A Cluster of Cases of Severe Acute Respiratory Syndrome in Hong Kong. N Engl J Med 2003, 348:1977-85. http://SARSReference.com/lit.php?id=12671062 http://SARSReference.com/lit.php?id=12671062 World Health Organization. (2004). Case Definition. Retrieved from: www.who.int/csr/sars/casedefinition/en/ www.who.int/csr/sars/casedefinition/en/ World Health Organization. (2004). Diagnostic Tests. Retrieved from www.who.int/csr/sars/diagnostictests/en/ www.who.int/csr/sars/diagnostictests/en/